1. Field of the Invention
This invention relates to a medical diagnostic device that is prepared by nonimpact printing; more particularly, by nonimpact printing of a reagent onto a hydrophilic surface of the device.
2. Description of the Related Art
A variety of medical diagnostic procedures involve tests on biological fluids, such as blood, urine, or saliva, and are based on a change in a physical characteristic of such a fluid or an element of the fluid, such as blood serum. The characteristic can be an electrical, magnetic, fluidic, or optical property. When an optical property is monitored, these procedures may make use of a transparent or translucent device to contain the biological fluid and a reagent. A change in light absorption of the fluid can be related to an analyte concentration in, or property of, the fluid. Typically, a light source is located adjacent to one surface of the device and a detector is adjacent to the opposite surface. The detector measures light transmitted through a fluid sample. Alternatively, the light source and detector can be on the same side of the device, in which case the detector measures light scattered and/or reflected by the sample. Finally, a reflector may be located at or adjacent to the opposite surface. A device of this latter type, in which light is first transmitted through the sample area, then reflected through a second time, is called a xe2x80x9ctransflectancexe2x80x9d device. References to xe2x80x9clightxe2x80x9d throughout this specification and the appended claims should be understood to include the infrared and ultraviolet spectra, as well as the visible. References to xe2x80x9cabsorptionxe2x80x9d are meant to refer to the reduction in intensity as a light beam passes through a medium; thus, it encompasses both xe2x80x9ctruexe2x80x9d absorption and scattering.
An example of a transparent test device is described in Wells et al. W094/02850, published on Feb. 3, 1994. Their device comprises a sealed housing, which is transparent or translucent, impervious, and rigid or semi-rigid. An assay material is contained within the housing, together with one or more assay reagents at predetermined sites. The housing is opened and the sample introduced just before conducting the assay. The combination of assay reagents and analyte in the sample results in a change in optical properties, such as color, of selected reagents at the end of the assay. The results can be read visually or with an optical instrument.
U.S. Pat. No. 3,620,676, issued on Nov. 16, 1971 to Davis, discloses a colorimetric indicator for liquids. The indicator includes a xe2x80x9chalf-bulb cavityxe2x80x9d, which is compressible. The bulb is compressed and released to form a suction that draws fluid from a source, through a half-tubular cavity that has an indicator imprinted on its wall. The only controls on fluid flow into the indicator are how much the bulb is compressed and how long the indicator inlet is immersed in the source, while the bulb is released.
U.S. Pat. No. 3,640,267, issued on Feb. 8, 1972 to Hurtig et al., discloses a container for collecting samples of body fluid that includes a chamber that has resilient, collapsible walls. The walls are squeezed before the container inlet is placed into the fluid being collected. When released, the walls are restored to their uncollapsed condition, drawing fluid into and through the inlet. As with the Davis device, discussed above, control of fluid flow into the indicator is very limited.
U.S. Pat. No. 4,088,448, issued on May 9, 1978 to Lilja et al., discloses a cuvette, which permits optical analysis of a sample mixed with a reagent. The reagent is coated on the walls of a cavity, which is then filled with a liquid sample. The sample mixes with the reagent to cause an optically-detectable change.
The test devices described above and in the cited references typically comprise a dry strip having a reagent coated on one or more predetermined positions. Applying these reagents to their intended positions on large numbers of these devices can, in principle, be accomplished by standard printing processes; however, nonimpact printing provides some distinct advantages. For example, nonimpact printers can be smaller, lighter, and less expensive, since they don""t have to endure the repeated impact of print head on substrate. They also permit the use of transparent substrates, as required for optical devices that involve changes in light transmission. Information on the varieties of nonimpact printing appears in J. L. Johnson, Principles of Nonimpact Printing, 3d ed., Palatino Press, Irvine, Calif. 1998. (See, also, xe2x80x9cNo-splatter spray makes better wafers,xe2x80x9d H. L. Berger, Machine Design, Feb. 5, 1998, pp. 52-55). Among the varieties of nonimpact printing, ink-jet printing has been identified as suitable for use in connection with reagent fluids.
British Patent Specification, 1,526,708, published on Sep. 27, 1978, discloses a reagent test device that comprises a carrier on which are printed two different substances, separated by a xe2x80x9cpredetermined interspace.xe2x80x9d Ink-jet printing is one of the printing techniques disclosed.
U.S. Pat. No. 4,877,745, issued on Oct. 31, 1989, to Hayes et al., discloses a system for printing reagents onto a printing medium by propelling droplets from a jetting tube and repeating the process until a desired configuration of the reagent is printed on the medium. A piezo-electric print head was used.
U.S. Pat. No. 5,108,926, issued on Apr. 28, 1992, to Klebe; discloses an apparatus for precisely locating cells on a substrate by using an ink-jet printer either to deposit the cells directly onto the substrate or to deposit cell adhesion materials. The ink-jet printer used was a Hewlett-Packard Thinkjet(trademark) printer, which is a thermal ink-jet printer (see Hewlett-Packard Journal, May, 1985).
U.S. Pat. No. 5,378,638, issued on Jan. 3, 1995, to Deeg et al., discloses an analysis element for the determination of an analyte in a liquid sample. The element is fabricated by ink-jet printing of reagents in a series of xe2x80x9ccompartments,xe2x80x9d using a thermal ink-jet print head.
Each of the references cited above are concerned, explicitly or implicitly, with image spreading on the print medium, because the sharpness of an image is degraded to the extent that the liquid xe2x80x9cinkxe2x80x9d spreads across the surface before drying. For diagnostic applications, sharp xe2x80x9cimagesxe2x80x9d are typically required, because different reagents are positioned close together on a surface of a device but must not come into contact (e.g., to react) until the device is wetted by an applied sample.
The present invention provides a method for preparing a medical diagnostic reagent device, comprising the steps of
a) providing a non-absorbent substrate, having on its surface at least one hydrophilic target area,
b) providing from a nonimpact print head onto a point within the target area a pulsed stream of microdroplets of a diagnostic reagent liquid,
c) moving the stream relative to the substrate, and
d) repeating steps b) and c) at least enough times to provide a substantially uniform layer of the liquid over the target area.
A diagnostic reagent device of the present invention measures analyte concentration or characteristic of a biological fluid and comprises
a) a sample application area for accepting a sample of the biological fluid for analysis and
b) a predetermined hydrophilic reagent area, onto which has been applied, by nonimpact printing, a diagnostic reagent liquid that interacts with the sample to cause in the sample a physically-measurable change that can be related to the analyte concentration or characteristic of the fluid.
The sample application and reagent areas may coincide or, alternatively, be spaced apart, with an intermediate path to convey the sample. The measurement is generally, but not necessarily, made when the sample is on the reagent area, and in the description below, the measurement of interest is made when the sample is in the reagent area.
The method is particularly well adapted for preparing a device for measuring prothrombin time (PT time), with the target area being coated with a reagent composition that catalyzes the blood clotting cascade. Similarly, the diagnostic reagent strip of the invention is particularly well adapted for measuring the PT time of a whole blood sample.
As used in this specification and the appended claims, the term xe2x80x9cmicrodrdpletxe2x80x9d refers to droplets having a volume in the range from about 1 picoliter to 1 microliter.
It is surprising that the hydrophilicity of the target area provides superior results, since the hydrophilic surface would be expected to spread the reagent that is deposited, which had been thought to be undesirable.